Many inborn errors of metabolism cause devastating neurologic disease. Representative of such disorders are the mucopolysaccharidoses (MPS), and specifically, beta-glucuronidase deficiency or MPS VII. Systemic treatments for the MPS have no effect on CNS involvement. Thus direct methods to correct the deficiency in brain should be developed, evaluated, and optimized. In the initial two years of funding of this award we have identified key limitations to efficacious application of adenoviral vectors to brain. Importantly, our data suggest that the limitations can be overcome, and that a therapeutic response can be achieved. Specifically, we hypothesize that increased transduction efficiency will improve efficacy of adenoviral mediated gone transfer in the CNS of gusmps/gusmps mice. Preliminary data using adenoviruses containing knobs from other serotypes support this hypothesis. Also, our data show that E4 deletion in the viral backbone, or transient inhibition of antigen presenting cell activation and T cell stimulation at the time of adenovirus vector delivery, significantly prolongs transgene expression. Finally, we hypothesize that transduction of cells responsible for moderating the constituents of the CSF, or targeting the vector to the vascular endothelium will increase the distribution of corrected cells to deficient mice and improve efficacy.